The most representative and better studied substances of this group are the nitrogen mustard derivatives, characterized by the 2-haloethyl amine group (Fig. 107) attached to a radical which can be aliphatic or aromatic. It seems that it is through hydrolysis that the compound becomes biologically active, and Haddow has shown that activity is present only if hydrolysis is sufficiently high. (62) The inequality of hydrolysis in different members can be related to the influence exerted by the radical bound to the nitrogen. It seems that the presence of a stronger energetic center, as it appears in positively or negatively charged atoms bound to the cyclic radical, reduces the dissociation of the chloroethyl group. Generally, nucleophilic groups would retard the dissociation. Sufficient evidence exists to show that biological activity follows the elimination of the chloride ion and the appearance of a carbonium ion as a reactive intermediate. A further passage into the ethyleneimonium ion, considered more stable and therefore less reactive, seems to complete the transformation. Figure 108 shows these changes.

The haloalkyl side chains in the molecule appear indispensable for biological activity. (63, 64, 65, 66) They lead to the immediate appearance of two positive electrostatic energedc centers. This does not represent a minimal condition, according to Landing and co workers. (67, 68) These investigators have shown that in nitrogen mustards, cytotoxicity increases with the number of haloalkyl side chains. It is to be noted that a double electrophilic center is found not only in the two original haloalkyl side chains, but also in the later product, the ethyleneimonium ion. In view of the more frequent appearance of this ion also for other agents, the analysis of the relationship of this group to twin formation appears interesting.

In the ethyleneimonium group, while a negative charge can be seen at the nitrogen, a positive charge appears to be present between the two CH3, providing a certain polarity. With two carbons positively charged and in a relatively fixed position, this group is similar energetically to a positive twin carbon group. A two step change, with the imonium group in the first, and a carbonium in the second, can explain, as we shall see below, the strange biological activity of the nitrogen mustards which have a carcinogenic activity only through changes which take place in the organism.

Nitrogen Mustard

Nitrogen Mustard

Fig. 107. The nitrogen mustard derivatives.

The changes occurring in the nitrogen mustardDielectrophilic


Fig. 108. The changes occurring in the nitrogen mustard leads to ethyleneimmonium in which an energetic aspect similar to that of a twin formation is present.

This agrees strongly with the nature of the more recently studied relatively active carcinogens, the ethyleneimines, where similar centers are seen. (Fig. 109) The biological effect of the ethyleneimine group has been considered to be related to a reactive intermediate.

Generally, if sufficient influence is exerted by another center in the molecule, the imine group becomes active. This center can be a nitro group as in 2:4 dinitrophenyl ethyleneimine, or other ethyleneimine groups as in methyleneimine 1:3:5 triazine. (Fig. 110) Through the influence exerted by these centers, the ethyleneimine group can have its carbons charged sufficiently to become a dielectrophilic formation. The possibility of a reactive intermediate and a more stable electrophilic form thus appears common to the two groups, mustards and ethyleneimines.

Triethylenimine 2 4 6  Triazine

Triethylenimine 2-4-6- Triazine

Fig. 109. Ethyleneimines are active carcinogens, probably related to their energetic aspect with a formation energetically similar to the twin formation.